Journal of Fluorine Chemistry (2009), 130 (10), 886-893 discloses 1-aryl-4-methyl-[1,2,4]triazolo[3,4-a]quinoxalines wherein aryl is phenyl, 4-methoxyphenyl, 4-chlorophenyl or 4-nitrophenyl, unexpectedly arising in a reaction of 2-hydrazine-3-methylquinoxaline with trifluoromethyl-beta-diketones.
Green Chemistry (2004), 6, 156-157 discloses solvent-free methods for the synthesis of 1-aryl-4-methyl-[1,2,4]triazolo[3,4-a]quinoxalines wherein aryl is phenyl, 4-methylphenyl, 4-chlorophenyl, 4-methoxyphenyl and 3-methoxyphenyl. Synthetic Communications (2006), 36, 1873-1878 discloses methods for the synthesis of 1-aryl-4-methyl-[1,2,4]triazolo[3,4-a]quinoxalines wherein aryl is phenyl, 4-methylphenyl, 4-chlorophenyl, 2-methoxyphenyl and 4-methoxyphenyl. WO-2010/101230 discloses [1,2,4]triazolo[4,3-a]quinoxalin-4(5H)-ones as PDE9 inhibitors useful for treating urination disorders.
Phosphodiesterases (PDEs) are a family of enzymes encoded by 21 genes and subdivided into 11 distinct families according to structural and functional properties.
These enzymes metabolically inactivate widely occurring intracellular second messengers, 3′,5′-cyclic adenosine monophosphate (cAMP) and 3′,5′-cyclic guanosine monophosphate (cGMP). These two messengers regulate a wide variety of biological processes, including pro-inflammatory mediator production and action, ion channel function, muscle contraction, learning, differentiation, apoptosis, lipogenesis, glycogenolysis, and gluconeogenesis. They do this by activation of protein kinase A (PKA) and protein kinase G (PKG), which in turn phosphorylate a wide variety of substrates including transcription factors and ion channels that regulate innumerable physiological responses. In neurons, this includes the activation of cAMP and cGMP-dependent kinases and subsequent phosphorylation of proteins involved in acute regulation of synaptic transmission as well as in neuronal differentiation and survival. Intracellular concentrations of cAMP and cGMP are strictly regulated by the rate of biosynthesis by cyclases and by the rate of degradation by PDEs. PDEs are hydrolases that inactivate cAMP and cGMP by catalytic hydrolysis of the 3′-ester bond, forming the inactive 5′-monophosphate (Scheme A).

On the basis of substrate specificity, the PDE families can be divided into three groups: i) the cAMP-specific PDEs, which include PDE4, 7 and 8; ii) the cGMP-selective enzymes PDE5, 6 and 9; and iii) the dual-substrate PDEs, PDE1, 2 and 3, as well as PDE10 and 11.
Furthermore, PDEs are expressed differentially throughout the organism, including the central nervous system. Different PDE isozymes therefore may have different physiological functions. Compounds that inhibit selectively PDE families or isozymes may display particular therapeutic activity, fewer side effects, or both.
Phosphodiesterase 2A (PDE2A) inactivates intracellular signalling mechanisms reliant on cyclic nucleotide signalling mediated by cAMP and cGMP via their degradation.
Such signalling pathways are known to play a role in the regulation of genes involved in the induction of synaptic plasticity.
The pharmacological inhibition of PDE2 therefore causes increased levels of synaptic plasticity (an underlying correlate of learning and memory), suggesting that PDE2A modulation may be a target for alleviating cognitive deficits seen in people suffering from disorders such as for example, schizophrenia, Alzheimer's disease, Parkinson's disease and other CNS disorders associated with cognitive dysfunction.
Phosphodiesterase 2A (PDE2A) is more abundantly expressed in the brain relative to peripheral tissues. The high expression of PDE2 in the limbic system (isocortex, hippocampus, amygdala, habenula, basal ganglia) suggests that PDE2 may modulate neuronal signalling involved in emotion, perception, concentration, learning and memory. Additionally, PDE2 is expressed in the nucleus accumbens, the olfactory bulb, the olfactory tubercle and the amygdala, supporting the suggestion that PDE2 may also be involved in anxiety and depression.
Additionally, PDE2 inhibitors have been shown to be beneficial in the reduction of oxidative stress-induced anxiety, supporting their use in the treatment of anxiety in neuropsychiatric and neurodegenerative disorders that involve oxidative stress, such as Alzheimer's disease, Parkinson's disease and multiple sclerosis.
PDE2 inhibitors have been shown to enhance long term potentiation of synaptic transmission and to improve memory acquisition and consolidation in the object recognition and in the social recognition tests in rats. Furthermore, PDE2 inhibitors have been shown to reverse the MK-801 induced working memory deficit in the T-maze in mice. PDE2 inhibitors have also been shown to display activity in forced swim test and light/dark box models; and to show anxiolytic-like effects in elevated plus-maze, hole-board and open-field tests and to prevent stress-induced changes in apoptosis and behaviour.
Thus, PDE2 inhibitors may be useful in the treatment of memory deficiency, cognitive disorders, anxiety, bipolar disorder and depression.
Of all the 11 known PDE families, PDE10 has the most restricted distribution with high expression only in the brain and testes. In the brain, PDE10A mRNA and protein are highly expressed in a majority of striatal Medium Spiny Neurons (MSNs). This unique distribution of PDE10A in the brain, together with its increased pharmacological characterization, indicates a potential use of PDE10A inhibitors for treating neurological and psychiatric disorders like schizophrenia.
Thus, PDE10 inhibitors may possess a pharmacological profile similar to that of the current antipsychotics which mainly treat positive symptoms of schizophrenia, but also having the potential to improve the negative and cognitive symptoms of schizophrenia, while lacking the non-target related side effects such as EPS or prolactin release, that are often observed with the currently available antipsychotics.
Since PDE10 inhibitors can be used to raise levels of cAMP and/or cGMP within cells that express the PDE10 enzyme, for example neurons that comprise the basal ganglia, PDE10 inhibitors may be useful in treating schizophrenia and additionally, a variety of conditions as described herein, for example, Parkinson's Disease, Huntington's Disease, addiction and depression. PDE10 inhibitors may be also useful in other conditions such as obesity, non-insulin dependent diabetes, bipolar disorder, obsessive compulsive disorder and pain.
While PDE2 inhibitors may provide an advantageous balance of properties in the treatment of disorders selected from, but not limited to, cognitive disorders, anxiety, depression, and movement disorders; compounds that are PDE2 and PDE10 inhibitors may show utility in schizophrenia, Parkinson's disease, Huntington's disease, addiction, depression, and anxiety, with an additional beneficial effect in cognitive deficits and/or drug-induced extrapyramidal symptoms observed in these patient populations.